Response inhibition (RI) is central to executive control of behavior, and multiple lines of evidence indicate that the locus coeruleus-norepinephrine (LC-NE) system is involved in RI. Specific cortical areas are also strongly implicated in RI, including a major target of LC neurons in rat, the orbitofrontal cortex (OFC). The go-nogo (GNG) and stop signal (SS) tasks are used to examine the neural substrates of response-restraint and response-cancellation, respectively. Importantly, these tasks are nearly identical in humans and rats. Moreover, NE actions in frontal cortical areas of both rats and humans are involved in RI, as well as in RI deficits in attention deficit disorder/hyperactivity (ADHD) subjects. These findings afford us the opportunity to conduct translationally relevant studies to examine the specific role of the NE-LC system and OFC in RI. We will obtain unit recordings from rat LC and OFC neurons during GNG and SS tasks to identify their roles in RI. Specifically, we will test the hypothesis that phasic activation of LC neurons, and NE actions in OFC, are importantly involved in these measures of inhibitory control. The selective NE reuptake inhibitor, atomoxetine (ATM), has recently been found effective for improving RI in normal and ADHD individuals. We hypothesize that this might be due, at least in part, to effects of this compound on the activity profile of LC neurons as well as its effect on LC-NE input to OFC cells. We will test this by recording LC and OFC neurons during GNG or SS tasks following ATM administration. Finally, we will use novel viral transduction methods to express the photosensitive cation channel channelrhodopsin-2, or choride pump halorhodopsin-3, selectively in LC-NE neurons. We will phasically photo-activate or -inhibit these cells, or their terminals in OFC, at specific points in these tasks to test a causal role for the NE-LC system and OFC in RI function. These proposed studies will substantially advance our understanding of inhibitory control through novel analyses of the contribution of the LC-NE system and OFC to RI task performance. The results of these studies will also provide a new approach to the design of drugs to treat human disorders involving impaired RI, including ADHD and drug addiction. PUBLIC HEALTH RELEVANCE: Response inhibition (RI) is an important cognitive function, and many disorders include an inability to inhibit inappropriate behavioral responses (e.g., attention deficit/hyperactivity disorder, obsessive-compulsive disorder and drug addiction). The proposed experiments will define the roles of key brain neurons in RI. This will facilitate development of better treatments for behavioral disorders that include deficient RI.